IMULDOSA 90mg 90mg / ml injection solution in pre-filled syringe medication leaflet

IMULDOSA 45 mg solution for injection in pre-filled syringe

IMULDOSA 90 mg solution for injection in pre-filled syringe

IMULDOSA 45 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 45 mg ustekinumab in 0.5 mL.

IMULDOSA 90 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 90 mg ustekinumab in 1 mL.

Ustekinumab is a fully human IgG1κ monoclonal antibody to interleukin (IL)-12/23 produced in a murinemyeloma cell line using recombinant DNA technology.

Each unit volume contains 0.02 mg of polysorbate 80; which is equivalent to 0.02 mg per 45 mg dose

Each unit volume contains 0.05 mg of polysorbate 80; which is equivalent to 0.04 mg per 90 mg dose

For the full list of excipients, see section 6.1.

IMULDOSA 45 mg solution for injection in pre-filled syringe (solution for injection)

IMULDOSA 90 mg solution for injection in pre-filled syringe (solution for injection)

The solution is colourless to slightly yellow and clear to slightly opalescent.

Plaque psoriasis

IMULDOSA is indicated for the treatment of moderate to severe plaque psoriasis in adults who failed to respondto, or who have a contraindication to, or are intolerant to other systemic therapies including ciclosporin,methotrexate (MTX) or PUVA (psoralen and ultraviolet A) (see section 5.1).

IMULDOSA is indicated for the treatment of moderate to severe plaque psoriasis in children and adolescentpatients from the age of 6 years and older, who are inadequately controlled by, or are intolerant to, other systemictherapies or phototherapies (see section 5.1).

Psoriatic arthritis (PsA)

IMULDOSA, alone or in combination with MTX, is indicated for the treatment of active psoriatic arthritis inadult patients when the response to previous non-biological disease- modifying anti-rheumatic drug (DMARD)therapy has been inadequate (see section 5.1).

Crohn’s Disease

IMULDOSA is indicated for the treatment of adult patients with moderately to severely active Crohn’s diseasewho have had an inadequate response with, lost response to, or were intolerant to either conventional therapy ora TNFα antagonist or have medical contraindications to such therapies.

IMULDOSA is intended for use under the guidance and supervision of physicians experienced in the diagnosisand treatment of conditions for which IMULDOSA is indicated.

Plaque psoriasis

The recommended posology of IMULDOSA is an initial dose of 45 mg administered subcutaneously, followedby a 45 mg dose 4 weeks later, and then every 12 weeks thereafter.

Consideration should be given to discontinuing treatment in patients who have shown no response up to 28 weeksof treatment.

Patients with body weight > 100 kg

For patients with a body weight > 100 kg the initial dose is 90 mg administered subcutaneously, followed by a90 mg dose 4 weeks later, and then every 12 weeks thereafter. In these patients, 45 mg was also shown to beefficacious. However, 90 mg resulted in greater efficacy (see section 5.1, Table 3).

Psoriatic arthritis (PsA)

The recommended posology of IMULDOSA is an initial dose of 45 mg administered subcutaneously, followedby a 45 mg dose 4 weeks later, and then every 12 weeks thereafter. Alternatively, 90 mg may be used in patientswith a body weight > 100 kg.

Consideration should be given to discontinuing treatment in patients who have shown no response up to 28 weeksof treatment.

No dose adjustment is needed for elderly patients (see section 4.4).

Ustekinumab has not been studied in these patient populations. No dose recommendations can be made.

The safety and efficacy of ustekinumab in children with psoriasis less than 6 years of age or in children withpsoriatic arthritis less than 18 years of age have not yet been established.

Paediatric plaque psoriasis (6 years and older)

The recommended dose of IMULDOSA based on body weight over 60 kg is shown below (Table 1). IMULDOSAshould be administered at Weeks 0 and 4, then every 12 weeks thereafter.

Table 1: Recommended dose of IMULDOSA for paediatric psoriasis

Body weight at the time of dosing Recommended Dose< 60 kg* -≥ 60-≤ 100 kg 45 mg> 100 kg 90 mg

* IMULDOSA is not available for patients that require less than a full 45 mg dose. If an alternativedose is required, other ustekinumab products offering such an option should be used.

There is no dose form for IMULDOSA that allows weight-based dosing for paediatric patients below 60 kg.

Patients weighing less than 60 kg should be accurately dosed on a mg/kg basis using another ustekinumab product,45 mg solution for injection in vials offering weight-based dosing instead.

Consideration should be given to discontinuing treatment in patients who have shown no response up to 28 weeksof treatment.

Crohn’s Disease

In the treatment regimen, the first dose of IMULDOSA is administered intravenously. For the posology ofthe intravenous dosing regimen, see section 4.2 of the IMULDOSA 130 mg Concentrate for solution forinfusion SmPC.

The first subcutaneous administration of 90 mg IMULDOSA should take place at week 8 after the intravenousdose. After this, dosing every 12 weeks is recommended.

Patients who have not shown adequate response at 8 weeks after the first subcutaneous dose, may receive asecond subcutaneous dose at this time (see section 5.1).

Patients who lose response on dosing every 12 weeks may benefit from an increase in dosing frequency to every8 weeks (see section 5.1, section 5.2).

Patients may subsequently be dosed every 8 weeks or every 12 weeks according to clinical judgment (see section5.1).

Consideration should be given to discontinuing treatment in patients who show no evidence of therapeutic benefit16 weeks after the IV induction dose or 16 weeks after switching to the 8-weekly maintenance dose.

Immunomodulators and/or corticosteroids may be continued during treatment with IMULDOSA. In patients whohave responded to treatment with IMULDOSA, corticosteroids may be reduced or discontinued in accordancewith standard of care.

In Crohn’s disease, if therapy is interrupted, resumption of treatment with subcutaneous dosing every 8 weeks issafe and effective.

No dose adjustment is needed for elderly patients (see section 4.4).

Ustekinumab has not been studied in these patient populations. No dose recommendations can be made.

The safety and efficacy of ustekinumab in treatment of Crohn’s disease in children less than 18 years have not yetbeen established. No data are available.

IMULDOSA 45 mg and 90 mg pre-filled syringes are for subcutaneous injection only. If possible, areas of theskin that show psoriasis should be avoided as injection sites.

After proper training in subcutaneous injection technique, patients or their caregivers may inject IMULDOSA ifa physician determines that it is appropriate. However, the physician should ensure appropriate follow-up ofpatients. Patients or their caregivers should be instructed to inject the prescribed amount of IMULDOSAaccording to the directions provided in the package leaflet.

Comprehensive instructions for administration are given in the package leaflet.

For further instructions on preparation and special precautions for handling, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Clinically important, active infection (e.g. active tuberculosis; see section 4.4).

In order to improve the traceability of biological medicinal products, the tradename and the batch number of theadministered product should be clearly recorded.

Ustekinumab may have the potential to increase the risk of infections and reactivate latent infections. In clinicalstudies and a post-marketing observational study in patients with psoriasis, serious bacterial, fungal, and viralinfections have been observed in patients receiving ustekinumab (see section 4.8).

Opportunistic infections including reactivation of tuberculosis, other opportunistic bacterial infections (includingatypical mycobacterial infection, listeria meningitis, pneumonia legionella, and nocardiosis), opportunistic fungalinfections, opportunistic viral infections (including encephalitis caused by herpes simplex 2), and parasiticinfections (including ocular toxoplasmosis) have been reported in patients treated with ustekinumab.

Caution should be exercised when considering the use of IMULDOSA in patients with a chronic infection or ahistory of recurrent infection (see section 4.3).

Prior to initiating treatment with IMULDOSA, patients should be evaluated for tuberculosis infection.

IMULDOSA must not be given to patients with active tuberculosis (see section 4.3). Treatment of latenttuberculosis infection should be initiated prior to administering IMULDOSA. Anti-tuberculosis therapy shouldalso be considered prior to initiation of IMULDOSA in patients with a history of latent or active tuberculosis inwhom an adequate course of treatment cannot be confirmed. Patients receiving IMULDOSA should bemonitored closely for signs and symptoms of active tuberculosis during and after treatment.

Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infection occur. If apatient develops a serious infection, the patient should be closely monitored and IMULDOSA should not beadministered until the infection resolves.

Immunosuppressants like ustekinumab have the potential to increase the risk of malignancy. Some patients whoreceived ustekinumab in clinical studies and in a post-marketing observational study in patients with psoriasisdeveloped cutaneous and non-cutaneous malignancies (see section 4.8). The risk of malignancy may be higher inpsoriasis patients who have been treated with other biologics during the course of their disease.

No studies have been conducted that include patients with a history of malignancy or that continue treatment inpatients who develop malignancy while receiving ustekinumab. Thus, caution should be exercised whenconsidering the use of IMULDOSA in these patients.

All patients, in particular those greater than 60 years of age, patients with a medical history of prolongedimmunosuppressant therapy or those with a history of PUVA treatment, should be monitored for the appearanceof skin cancer (see section 4.8).

Systemic and respiratory hypersensitivity reactions

Systemic

Serious hypersensitivity reactions have been reported in the post-marketing setting, in some cases several daysafter treatment. Anaphylaxis and angioedema have occurred. If an anaphylactic or other serious hypersensitivityreaction occurs, appropriate therapy should be instituted and administration of IMULDOSA should bediscontinued (see section 4.8).

Respiratory

Cases of allergic alveolitis, eosinophilic pneumonia, and non-infectious organising pneumonia have beenreported during post-approval use of ustekinumab. Clinical presentations included cough, dyspnoea, andinterstitial infiltrates following one to three doses. Serious outcomes have included respiratory failure andprolonged hospitalisation. Improvement has been reported after discontinuation of ustekinumab and also, in somecases, administration of corticosteroids. If infection has been excluded and diagnosis is confirmed, discontinueustekinumab and institute appropriate treatment (see section 4.8).

Cardiovascular events including myocardial infarction and cerebrovascular accident have been observed inpatients with psoriasis exposed to ustekinumab in a post-marketing observational study. Risk factors forcardiovascular disease should be regularly assessed during treatment with ustekinumab.

It is recommended that live viral or live bacterial vaccines (such as Bacillus of Calmette and Guérin (BCG))should not be given concurrently with IMULDOSA. Specific studies have not been conducted in patients whohad recently received live viral or live bacterial vaccines. No data are available on the secondary transmission ofinfection by live vaccines in patients receiving ustekinumab. Before live viral or live bacterial vaccination,treatment with IMULDOSA should be withheld for at least 15 weeks after the last dose and can be resumed atleast 2 weeks after vaccination. Prescribers should consult the Summary of Product Characteristics for thespecific vaccine for additional information and guidance on concomitant use of immunosuppressive agents post-vaccination.

Administration of live vaccines (such as the BCG vaccine) to infants exposed in utero to ustekinumab is notrecommended for twelve months following birth or until ustekinumab infant serum levels are undetectable (seesections 4.5 and 4.6). If there is a clear clinical benefit for the individual infant, administration of a live vaccinemight be considered at an earlier timepoint, if infant ustekinumab serum levels are undetectable.

Patients receiving IMULDOSA may receive concurrent inactivated or non-live vaccinations.

Long term treatment with ustekinumab does not suppress the humoral immune response to pneumococcalpolysaccharide or tetanus vaccines (see section 5.1).

Concomitant immunosuppressive therapy

In psoriasis studies, the safety and efficacy of ustekinumab in combination with immunosuppressants, includingbiologics, or phototherapy have not been evaluated. In psoriatic arthritis studies, concomitant MTX use did notappear to influence the safety or efficacy of ustekinumab. In Crohn’s disease studies, concomitant use ofimmunosuppressants or corticosteroids did not appear to influence the safety or efficacy of ustekinumab. Cautionshould be exercised when considering concomitant use of other immunosuppressants and IMULDOSA or whentransitioning from other immunosuppressive biologics (see section 4.5).

Immunotherapy

Ustekinumab has not been evaluated in patients who have undergone allergy immunotherapy. It is not knownwhether ustekinumab may affect allergy immunotherapy.

Serious skin conditions

In patients with psoriasis, exfoliative dermatitis has been reported following ustekinumab treatment (see section4.8). Patients with plaque psoriasis may develop erythrodermic psoriasis, with symptoms that may be clinicallyindistinguishable from exfoliative dermatitis, as part of the natural course of their disease. As part of themonitoring of the patient’s psoriasis, physicians should be alert for symptoms of erythrodermic psoriasis orexfoliative dermatitis. If these symptoms occur, appropriate therapy should be instituted. IMULDOSA should bediscontinued if a drug reaction is suspected.

Lupus-related conditions

Cases of lupus-related conditions have been reported in patients treated with ustekinumab, including cutaneouslupus erythematosus and lupus-like syndrome. If lesions occur, especially in sun exposed areas of the skin or ifaccompanied by arthralgia, the patient should seek medical attention promptly. If the diagnosis of a lupus-relatedcondition is confirmed, ustekinumab should be discontinued and appropriate treatment initiated.

No overall differences in efficacy or safety in patients aged 65 and older who received ustekinumab wereobserved compared to younger patients in clinical studies in approved indications, however the number ofpatients aged 65 and older is not sufficient to determine whether they respond differently from younger patients.

Because there is a higher incidence of infections in the elderly population in general, caution should be used intreating the elderly.

Polysorbate content 80

IMULDOSA contains 0.02 mg polysorbate 80 in each unit volume, which is equivalent to 0.02 mg per45 mg dose.

IMULDOSA contains 0.05 mg polysorbate 80 in each unit volume, which is equivalent to 0.04 mg per90 mg dose.

Polysorbates may cause allergic reactions. Tell your doctor if you have any known allergies.

Live vaccines should not be given concurrently with IMULDOSA.

Administration of live vaccines (such as the BCG vaccine) to infants exposed in utero to ustekinumab is notrecommended for twelve months following birth or until ustekinumab infant serum levels are undetectable (seesections 4.4 and 4.6). If there is a clear clinical benefit for the individual infant, administration of a live vaccinemight be considered at an earlier timepoint, if infant ustekinumab serum levels are undetectable.

In the population pharmacokinetic analyses of the phase 3 studies, the effect of the most frequently usedconcomitant medicinal products in patients with psoriasis (including paracetamol, ibuprofen, acetylsalicylicacid, metformin, atorvastatin, levothyroxine) on pharmacokinetics of ustekinumab was explored. There were noindications of an interaction with these concomitantly administered medicinal products. The basis for thisanalysis was that at least 100 patients (> 5% of the studied population) were treated concomitantly with thesemedicinal products for at least 90% of the study period. The pharmacokinetics of ustekinumab was not impactedby concomitant use of MTX, NSAIDs, 6-mercaptopurine, azathioprine and oral corticosteroids in patients withpsoriatic arthritis, Crohn’s disease, or prior exposure to anti-TNFα agents, in patients with psoriatic arthritis or

The results of an in vitro study and a phase 1 study in subjects with active Crohn’s disease do not suggest the needfor dose adjustments in patients who are receiving concomitant CYP450 substrates (see section 5.2).

In psoriasis studies, the safety and efficacy of ustekinumab IMULDOSA in combination withimmunosuppressants, including biologics, or phototherapy have not been evaluated. In psoriatic arthritis studies,concomitant MTX use did not appear to influence the safety or efficacy of ustekinumab. In Crohn’s diseasestudies, concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety orefficacy of ustekinumab (see section 4.4).

Women of childbearing potential should use effective methods of contraception during treatment and for at least15 weeks after treatment.

Data from a moderate number of prospectively collected pregnancies following exposure to ustekinumab withknown outcomes, including more than 450 pregnancies exposed during the first trimester, do not indicate anincreased risk of major congenital malformations in the newborn.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetaldevelopment, parturition or postnatal development (see section 5.3).

However, the available clinical experience is limited. As a precautionary measure, it is preferable to avoid the useof IMULDOSA in pregnancy.

Ustekinumab crosses the placenta and has been detected in the serum of infants born to female patients treatedwith ustekinumab during pregnancy. The clinical impact of this is unknown, however, the risk of infection ininfants exposed in utero to ustekinumab may be increased after birth. Administration of live vaccines (such as the

BCG vaccine) to infants exposed in utero to ustekinumab is not recommended for twelve months following birthor until ustekinumab infant serum levels are undetectable (see sections 4.4 and 4.5). If there is a clear clinicalbenefit for the individual infant, administration of a live vaccine might be considered at an earlier timepoint, ifinfant ustekinumab serum levels are undetectable.

Limited data from published literature suggests that ustekinumab is excreted in human breast milk in very smallamounts. It is not known if ustekinumab is absorbed systemically after ingestion. Because of the potential foradverse reactions in nursing infants from ustekinumab, a decision on whether to discontinue breast-feeding duringtreatment and up to 15 weeks after treatment or to discontinue therapy with IMULDOSA must be made takinginto account the benefit of breast-feeding to the child and the benefit of IMULDOSA therapy to the woman.

The effect of ustekinumab on human fertility has not been evaluated (see section 5.3).

IMULDOSA has no or negligible influence on the ability to drive and use machines.

The most common adverse reactions (> 5%) in controlled periods of the adult psoriasis, psoriatic arthritis,

Crohn’s disease clinical studies with ustekinumab were nasopharyngitis and headache. Most were considered tobe mild and did not necessitate discontinuation of study treatment. The most serious adverse reaction that hasbeen reported for ustekinumab is serious hypersensitivity reactions including anaphylaxis (see section 4.4). Theoverall safety profile was similar for patients with psoriasis, psoriatic arthritis, Crohn’s disease.

The safety data described below reflect exposure in adults to ustekinumab in 14 phase 2 and phase 3 studies in6,710 patients (4,135 with psoriasis and/or psoriatic arthritis and 1,749 with Crohn’s disease). This includesexposure to ustekinumab in the controlled and non-controlled periods of the clinical studies in patients withpsoriasis, psoriatic arthritis, Crohn’s disease for at least 6 months (4,577 patients) or at least 1 year (3,648patients). 2,194 patients with psoriasis, and Crohn’s disease for at least 4 years while 1,148 patients with psoriasisor Crohn’s disease were exposed for at least 5 years.

Table 2 provides a list of adverse reactions from adult psoriasis, psoriatic arthritis and Crohn’s disease clinicalstudies as well as adverse reactions reported from post-marketing experience. The adverse reactions are classifiedby System Organ Class and frequency, using the following convention: Very common (≥ 1/10), Common (≥1/100 to < 1/10), Uncommon (≥ 1/1,000 to < 1/100), Rare (≥ 1/10,000 to < 1/1,000), Very rare (< 1/10,000), notknown (cannot be estimated from the available data). Within each frequency grouping, adverse reactions arepresented in order of decreasing seriousness.

Table 2: List of adverse reactions

System Organ Class Frequency: Adverse reaction

Infections and infestations Common: Upper respiratory tract infection, nasopharyngitis,sinusitis

Uncommon: Cellulitis, dental infections, herpes zoster, lowerrespiratory tract infection, viral upper respiratory tract infection,vulvovaginal mycotic infection

Immune system disorders Uncommon: Hypersensitivity reactions (including rash, urticaria)

Rare: Serious hypersensitivity reactions (including anaphylaxis,angioedema)

Psychiatric disorders Uncommon: Depression

Nervous system disorders Common: Dizziness, headache

Uncommon: Facial palsy

Respiratory, thoracic and Common: Oropharyngeal painmediastinal disorders Uncommon: Nasal congestion

Rare: Allergic alveolitis, eosinophilic pneumonia

Very rare: Organising pneumonia*

Gastrointestinal disorders Common: Diarrhoea, nausea, vomiting

Skin and subcutaneous tissue Common: Pruritusdisorders Uncommon: Pustular psoriasis, skin exfoliation, acne

Rare: Exfoliative dermatitis, hypersensitivity vasculitis

Very rare: Bullous pemphigoid, cutaneous lupuserythematosus

Musculoskeletal and connective Common: Back pain, myalgia, arthralgiatissue disorders Very rare: Lupus-like syndrome

General disorders and Common: Fatigue, injection site erythema, injection site painadministration site conditions Uncommon: Injection site reactions (including haemorrhage,haematoma, induration, swelling and pruritus), asthenia

* See section 4.4, Systemic and respiratory hypersensitivity reactions.

In the placebo-controlled studies of patients with psoriasis, psoriatic arthritis and Crohn’s disease the rates ofinfection or serious infection were similar between ustekinumab- treated patients and those treated with placebo.

In the placebo-controlled period of these clinical studies, the rate of infection was 1.36 per patient-year offollow-up in ustekinumab-treated patients, and 1.34 in placebo-treated patients. Serious infections occurred atthe rate of 0.03 per patient-year of follow-up in ustekinumab-treated patients (30 serious infections in 930patient-years of follow-up) and 0.03 in placebo-treated patients (15 serious infections in 434 patient- years offollow-up) (see section 4.4).

In the controlled and non-controlled periods of psoriasis, psoriatic arthritis and Crohn’s disease clinical studies,representing 15,227 patient years of ustekinumab exposure in 6,710 patients, the median follow -upwas 1.2 years; 1.7 years for psoriatic disease studies, and 0.6 year for Crohn’s disease studies . Therate of infection was 0.85 per patient year of follow up in ustekinumab treated patients, and the rateof serious infections was 0.02 per patient year of follow up in ustekinumab treated patients (289serious infections in 15,227 patient years of follow up) and serious infections reported includedpneumonia, anal abscess, cellulitis, diverticulitis, gastroenteritis and viral infections.

In clinical studies, patients with latent tuberculosis who were concurrently treated with isoniazid did not developtuberculosis.

In the placebo-controlled period of the psoriasis, psoriatic arthritis and Crohn’s disease clinical studies, theincidence of malignancies excluding non-melanoma skin cancer was 0.11 per 100 patient-years of follow-up forustekinumab-treated patients (1 patient in 929 patient-years of follow-up) compared with 0.23 for placebo-treatedpatients (1 patient in 434 patient-years of follow-up). The incidence of non-melanoma skin cancer was 0.43 per100 patient-years of follow-up for ustekinumab-treated patients (4 patients in 929 patient-years of follow-up)compared to 0.46 for placebo-treated patients (2 patients in 433 patient-years of follow-up).

In the controlled and non-controlled periods of psoriasis, psoriatic arthritis and Crohn’s disease clinical studies,representing 15,205 patient-years of ustekinumab exposure in 6,710 patients, the median follow-up was 1.2 years;1.7 years for psoriatic disease studies and 0.6 years for Crohn’s disease studies. Malignancies excluding nonmelanoma skin cancers were reported in 76 patients in 15,205 patient years of follow up (incidence of 0.50 per100 patient-years of follow-up for ustekinumab treated patients). The incidence of malignancies reported inustekinumab treated patients was comparable to the incidence expected in the general population (standardisedincidence ratio = 0.94 [95% confidence interval: 0.73, 1.18], adjusted for age, gender and race). The mostfrequently observed malignancies, other than non melanoma skin cancer, were prostate, melanoma, colorectal, andbreast cancers. The incidence of non melanoma skin cancer was 0.46 per 100 patient years of follow up forustekinumab treated patients (69 patients in 15,165 patient years of follow up). The ratio of patients with basalversus squamous cell skin cancers (3:1) is comparable with the ratio expected in the general population (seesection 4.4).

During the controlled periods of the psoriasis and psoriatic arthritis clinical studies of ustekinumab, rash andurticaria have each been observed in < 1% of patients (see section 4.4).

Paediatric patients 6 years and older with plaque psoriasis

The safety of ustekinumab has been studied in two phase 3 studies of paediatric patients with moderate tosevere plaque psoriasis. The first study was in 110 patients from 12 to 17 years of age treated for up to 60 weeksand the second study was in 44 patients from 6 to 11 years of age treated for up to 56 weeks. In general, theadverse events reported in these two studies with safety data up to 1 year were similar to those seen in previousstudies in adults with plaque psoriasis.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

Single doses up to 6 mg/kg have been administered intravenously in clinical studies without dose- limitingtoxicity. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms ofadverse reactions and appropriate symptomatic treatment be instituted immediately.

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC05

IMULDOSA is a biosimilar medicinal product. Detailed information is available on the website of the European

Medicines Agency http://www.ema.europa.eu

Ustekinumab is a fully human IgG1κ monoclonal antibody that binds with specificity to the shared p40 proteinsubunit of human cytokines interleukin (IL)-12 and IL-23. Ustekinumab inhibits the bioactivity of human IL-12and IL-23 by preventing p40 from binding to the IL-12Rβ1 receptor protein expressed on the surface of immunecells. Ustekinumab cannot bind to IL-12 or IL-23 that is already bound to IL-12Rβ1 cell surface receptors. Thus,ustekinumab is not likely to contribute to complement- or antibody-mediated cytotoxicity of cells with IL-12and/or IL-23 receptors. IL-12 and IL-23 are heterodimeric cytokines secreted by activated antigen presentingcells, such as macrophages and dendritic cells, and both cytokines participate in immune functions; IL-12stimulates natural killer (NK) cells and drives the differentiation of CD4+ T cells toward the T helper 1 (Th1)phenotype, IL-23 induces the T helper 17 (Th17) pathway. However, abnormal regulation of IL 12 and IL 23 hasbeen associated with immune mediated diseases, such as psoriasis, psoriatic arthritis, Crohn’s disease.

By binding the shared p40 subunit of IL-12 and IL-23, ustekinumab may exert its clinical effects in psoriasis,psoriatic arthritis, Crohn’s disease through interruption of the Th1 and Th17 cytokine pathways, which are centralto the pathology of these diseases.

In patients with Crohn’s disease, treatment with ustekinumab resulted in a decrease in inflammatory markersincluding C-Reactive Protein (CRP) and fecal calprotectin during the induction phase, which were thenmaintained throughout the maintenance phase. CRP was assessed during the study extension and the reductionsobserved during maintenance were generally sustained through week 252.

During the long-term extension of Psoriasis Study 2 (PHOENIX 2), adult patients treated with ustekinumab for atleast 3.5 years mounted similar antibody responses to both pneumococcal polysaccharide and tetanus vaccinesas a non-systemically treated psoriasis control group. Similar proportions of adult patients developed protectivelevels of anti-pneumococcal and anti- tetanus antibodies and antibody titres were similar among ustekinumab-treated and control patients.

Plaque psoriasis (Adults)

The safety and efficacy of ustekinumab was assessed in 1,996 patients in two randomised, double-blind, placebo-controlled studies in patients with moderate to severe plaque psoriasis and who were candidates for phototherapyor systemic therapy. In addition, a randomised, blinded assessor, active-controlled study compared ustekinumaband etanercept in patients with moderate to severe plaque psoriasis who had had an inadequate response to,intolerance to, or contraindication to ciclosporin, MTX, or PUVA.

Psoriasis Study 1 (PHOENIX 1) evaluated 766 patients. 53% of these patients were either non- responsive,intolerant, or had a contraindication to other systemic therapy. Patients randomized to ustekinumab received 45mg or 90 mg doses at Weeks 0 and 4 and followed by the same dose every 12 weeks. Patients randomised toreceive placebo at Weeks 0 and 4 crossed over to receive ustekinumab (either 45 mg or 90 mg) at Weeks 12 and16 followed by dosing every 12 weeks. Patients originally randomised to ustekinumab who achieved Psoriasis

Area and Severity Index 75 response (PASI improvement of at least 75% relative to baseline) at both Weeks 28and 40 were re-randomised to receive ustekinumab every 12 weeks or to placebo (i.e., withdrawal of therapy).

Patients who were re-randomised to placebo at week 40 reinitiated ustekinumab at their original dosing regimenwhen they experienced at least a 50% loss of their PASI improvement obtained at week 40. All patients werefollowed for up to 76 weeks following first administration of study treatment.

Psoriasis Study 2 (PHOENIX 2) evaluated 1,230 patients. 61% of these patients were either non- responsive,intolerant, or had a contraindication to other systemic therapy. Patients randomised to ustekinumab received 45mg or 90 mg doses at Weeks 0 and 4 followed by an additional dose at 16 weeks. Patients randomised to receiveplacebo at Weeks 0 and 4 crossed over to receive ustekinumab (either 45 mg or 90 mg) at Weeks 12 and 16. Allpatients were followed for up to 52 weeks following first administration of study treatment.

Psoriasis Study 3 (ACCEPT) evaluated 903 patients with moderate to severe psoriasis who inadequatelyresponded to, were intolerant to, or had a contraindication to other systemic therapy and compared the efficacyof ustekinumab to etanercept and evaluated the safety of ustekinumab and etanercept. During the 12-weekactive-controlled portion of the study, patients were randomised to receive etanercept (50 mg twice a week),ustekinumab 45 mg at Weeks 0 and 4, or ustekinumab 90 mg at Weeks 0 and 4.

Baseline disease characteristics were generally consistent across all treatment groups in Psoriasis Studies 1 and2 with a median baseline PASI score from 17 to 18, median baseline Body Surface Area (BSA) ≥ 20, and median

Dermatology Life Quality Index (DLQI) range from 10 to 12. Approximately one third (Psoriasis Study 1) andone quarter (Psoriasis Study 2) of subjects had Psoriatic Arthritis (PsA). Similar disease severity was also seen in

Psoriasis Study 3.

The primary endpoint in these studies was the proportion of patients who achieved PASI 75 response frombaseline at week 12 (see Tables 3 and 4).

Table 3: Summary of clinical response in Psoriasis Study 1 (PHOENIX 1) and Psoriasis Study 2 (PHOENIX 2)

Week 28

Week 123 doses (week 0,2 doses (week 0 and week 4)week 4 and week 16)

PBO 45 mg 90 mg 45 mg 90 mg

Psoriasis Study 1

Number of patients255 255 256 250 243randomised26 (10%) 213 (84%)a 220 (86%)a 228 (91%)

PASI 50 response N (%) (96%)8 (3%) 171 (67%)a 170 (66%)a 178 (71%)

PASI 75 response N (%) (79%)

PASI 90 response N (%) 1355 (2%) 106 (42%)a 94 (37%)a 123 (49%)(56%)

PGAb of cleared or 16010 (4%) 151 (59%)a 156 (61%)a 146 (58%)minimal N (%) (66%)

Number of patients166 168 164 164 153≤ 100 kg

PASI 75 response N (%) 1246 (4%) 124 (74%) 107 (65%) 130 (79%)(81%)

Number of patients89 87 92 86 90> 100 kg

PASI 75 response N (%) 2 (2%) 47 (54%) 63 (68%) 48 (56%) 67 (74%)

Psoriasis Study 2

Number of patients410 409 411 397 400randomised41 (10%) 342 (84%)a 367 (89%)a 369 (93%)

PASI 50 response N (%) (95%)15 (4%) 273 (67%)a 311 (76%)a 276 (70%)

PASI 75 response N (%) (79%)

PASI 90 response N (%) 2173 (1%) 173 (42%)a 209 (51%)a 178 (45%)(54%)

PGAb of cleared or a a 27918 (4%) 277 (68%) 300 (73%) 241 (61%)minimal N (%) (70%)

Number of patients290 297 289 287 280≤ 100 kg

PASI 75 response N (%) 22612 (4%) 218 (73%) 225 (78%) 217 (76%)(81%)

Number of patients120 112 121 110 119> 100 kg

PASI 75 response N (%) 3 (3%) 55 (49%) 86 (71%) 59 (54%) 88 (74%)a p < 0.001 for ustekinumab 45 mg or 90 mg in comparison with placebo (PBO).b PGA = Physician Global Assessment

Table 4: Summary of clinical response at week 12 in Psoriasis Study 3 (ACCEPT)

Psoriasis Study 3

Etanercept Ustekinumab24 doses 2 doses (week 0 and week 4)(50 mg twice a week)45 mg 90 mg

Number of patients randomised 347 209 347

PASI 50 response N (%) 286 (82%) 181 (87%) 320 (92%)a

PASI 75 response N (%) 197 (57%) 141 (67%)b 256 (74%)a

PASI 90 response N (%) 80 (23%) 76 (36%)a 155 (45%)a

PGA of cleared or minimal N (%) 170 (49%) 136 (65%)a 245 (71%)a

Number of patients ≤ 100 kg 251 151 244

PASI 75 response N (%) 154 (61%) 109 (72%) 189 (77%)

Number of patients > 100 kg 96 58 103

PASI 75 response N (%) 43 (45%) 32 (55%) 67 (65%)a p < 0.001 for ustekinumab 45 mg or 90 mg in comparison with etanercept.

b p = 0.012 for ustekinumab 45 mg in comparison with etanercept.

In Psoriasis Study 1 maintenance of PASI 75 was significantly superior with continuous treatment comparedwith treatment withdrawal (p < 0.001). Similar results were seen with each dose of ustekinumab. At 1 year (week52), 89% of patients re-randomised to maintenance treatment were PASI 75 responders compared with 63% ofpatients re-randomised to placebo (treatment withdrawal) (p < 0.001). At 18 months (week 76), 84% of patientsre-randomised to maintenance treatment were PASI 75 responders compared with 19% of patients re-randomisedto placebo (treatment withdrawal). At 3 years (week 148), 82% of patients re-randomised to maintenancetreatment were PASI 75 responders. At 5 years (week 244), 80% of patients re- randomised to maintenancetreatment were PASI 75 responders.

In patients re-randomised to placebo, and who reinitiated their original ustekinumab treatment regimen after lossof ≥ 50% of PASI improvement 85% regained PASI 75 response within 12 weeks after re-initiating therapy.

In Psoriasis Study 1, at week 2 and week 12, significantly greater improvements from baseline weredemonstrated in the DLQI in each ustekinumab treatment group compared with placebo. The improvement wassustained through week 28. Similarly, significant improvements were seen in Psoriasis Study 2 at week 4 and 12,which were sustained through week 24. In Psoriasis Study 1, improvements in nail psoriasis (Nail Psoriasis

Severity Index), in the physical and mental component summary scores of the SF-36 and in the Itch Visual

Analogue Scale (VAS) were also significant in each ustekinumab treatment group compared with placebo. In

Psoriasis Study 2, the Hospital Anxiety and Depression Scale (HADS) and Work Limitations Questionnaire(WLQ) were also significantly improved in each ustekinumab treatment group compared with placebo.

Psoriatic arthritis (PsA) (Adults)

Ustekinumab has been shown to improve signs and symptoms, physical function and health- related quality oflife, and reduce the rate of progression of peripheral joint damage in adult patients with active PsA.

The safety and efficacy of ustekinumab was assessed in 927 patients in two randomised, double- blind,placebo-controlled studies in patients with active PsA (≥ 5 swollen joints and ≥ 5 tender joints) despite non-steroidal anti-inflammatory (NSAID) or disease modifying antirheumatic (DMARD) therapy. Patients in thesestudies had a diagnosis of PsA for at least 6 months. Patients with each subtype of PsA were enrolled,including polyarticular arthritis with no evidence of rheumatoid nodules (39%), spondylitis with peripheralarthritis (28%), asymmetric peripheral arthritis (21%), distal interphalangeal involvement (12%) and arthritismutilans (0.5%). Over 70% and 40% of the patients in both studies had enthesitis and dactylitis at baseline,respectively. Patients were randomised to receive treatment with ustekinumab 45 mg, 90 mg, or placebosubcutaneously at Weeks 0 and 4 followed by every 12 weeks (q12w) dosing. Approximately 50% of patientscontinued on stable doses of MTX (≤ 25 mg/week).

In PsA Study 1 (PSUMMIT I) and PsA Study 2 (PSUMMIT II), 80% and 86% of the patients, respectively, hadbeen previously treated with DMARDs. In Study 1 previous treatment with anti-tumour necrosis factor (TNF)αagent was not allowed. In Study 2, the majority of patients (58%, n = 180) had been previously treated with oneor more anti-TNFα agent(s), of whom over 70% had discontinued their anti-TNFα treatment for lack of efficacyor intolerance at any time.

Signs and symptoms

Treatment with ustekinumab resulted in significant improvements in the measures of disease activity comparedto placebo at week 24. The primary endpoint was the percentage of patients who achieved American College of

Rheumatology (ACR) 20 response at week 24. The key efficacy results are shown in Table 5 below.

Table 5: Number of patients who achieved clinical response in Psoriatic arthritis Study 1 (PSUMMIT I)and Study 2 (PSUMMIT II) at week 24

Psoriatic arthritis Study 1 Psoriatic arthritis Study 2

PBO 45 mg 90 mg PBO 45 mg 90 mg

Number ofpatients 206 205 204 104 103 105randomised

ACR 20 response, N(%) 47 (23%) 87 (42%)a 101 (50%)a 21 (20%) 45 (44%)a 46 (44%)a

ACR 50 response, N(%) 18 (9%) 51 (25%)a 57 (28%)a 7 (7%) 18 (17%)b 24 (23%)a

ACR 70 response, N(%) 5 (2%) 25 (12%)a 29 (14%)a 3 (3%) 7 (7%)c 9 (9%)c

Number of patientswith ≥ 3% BSAd 146 145 149 80 80 81

PASI 75 response, N(%) 16 (11%) 83 (57%)a 93 (62%)a 4 (5%) 41 (51%)a 45 (56%)a

PASI 90 response, N(%) 4 (3%) 60 (41%)a 65 (44%)a 3 (4%) 24 (30%)a 36 (44%)a

Combined PASI 75and ACR 20 8 (5%) 40 (28%)a 62 (42%)a 2 (3%) 24 (30%)a 31 (38%)aresponse, N (%)

Number of patients≤ 100 kg 154 153 154 74 74 73

ACR 20 response, N(%) 39 (25%) 67 (44%) 78 (51%) 17 (23%) 32 (43%) 34 (47%)

Number of patientswith ≥ 3% BSAd 105 105 111 54 58 57

PASI 75 response, N(%) 14 (13%) 64 (61%) 73 (66%) 4 (7%) 31 (53%) 32 (56%)

Number of patients> 100 kg 52 52 50 30 29 31

ACR 20 response, N(%) 8 (15%) 20 (38%) 23 (46%) 4 (13%) 13 (45%) 12 (39%)

Number of patientswith ≥ 3% BSAd 41 40 38 26 22 24

PASI 75 response, N(%) 2 (5%) 19 (48%) 20 (53%) 0 10 (45%) 13 (54%)a p < 0.001b p < 0.05c p = NSd Number of patients with ≥ 3% BSA psoriasis skin involvement at baseline

ACR 20, 50 and 70 responses continued to improve or were maintained through week 52 (PsA Study 1 and 2)and week 100 (PsA Study 1). In PsA Study 1, ACR 20 responses at week 100 were achieved by 57% and 64%, for45 mg and 90 mg, respectively. In PsA Study 2, ACR 20 responses at week 52 were achieved by 47% and 48%,for 45 mg and 90 mg, respectively.

The proportion of patients achieving a modified PsA response criteria (PsARC) response was also significantlygreater in the ustekinumab groups compared to placebo at week 24. PsARC responses were maintained throughweeks 52 and 100. A higher proportion of patients treated with ustekinumab who had spondylitis with peripheralarthritis as their primary presentation, demonstrated 50 and 70 percent improvement in Bath Ankylosing

Spondylitis Disease Activity Index (BASDAI) scores compared with placebo at week 24.

Responses observed in the ustekinumab treated groups were similar in patients receiving and not receivingconcomitant MTX, and were maintained through weeks 52 and 100. Patients previously treated with anti-TNFαagents who received ustekinumab achieved a greater response at week 24 than patients receiving placebo (ACR20 response at week 24 for 45 mg and 90 mg was 37% and 34%, respectively, compared with placebo 15%; p <0.05), and responses were maintained through week 52.

For patients with enthesitis and/or dactylitis at baseline, in PsA Study 1 significant improvement in enthesitisand dactylitis score was observed in the ustekinumab groups compared with placebo at week 24. In PsA Study 2significant improvement in enthesitis score and numerical improvement (not statistically significant) in dactylitisscore was observed in the ustekinumab 90 mg group compared with placebo at week 24. Improvements inenthesitis score and dactylitis score were maintained through weeks 52 and 100.

Radiographic Response

Structural damage in both hands and feet was expressed as change in total van der Heijde-Sharp score (vdH-Sscore), modified for PsA by addition of hand distal interphalangeal joints, compared to baseline. A pre-specifiedintegrated analysis combining data from 927 subjects in both PsA Study 1 and 2 was performed. Ustekinumabdemonstrated a statistically significant decrease in the rate of progression of structural damage compared toplacebo, as measured by change from baseline to week 24 in the total modified vdH-S score (mean ± SD scorewas 0.97 ± 3.85 in the placebo group compared with 0.40 ± 2.11 and 0.39 ± 2.40 in the ustekinumab 45 mg (p <0.05) and 90 mg (p < 0.001) groups, respectively). This effect was driven by PsA Study 1. The effect isconsidered demonstrated irrespective of concomitant MTX use, and was maintained through Weeks 52(integrated analysis) and 100 (PsA Study 1).

Ustekinumab-treated patients showed significant improvement in physical function as assessed by the Disability

Index of the Health Assessment Questionnaire (HAQ-DI) at week 24. The proportion of patients achieving aclinically meaningful ≥ 0.3 improvement in HAQ-DI score from baseline was also significantly greater in theustekinumab groups when compared with placebo. Improvement in HAQ-DI score from baseline was maintainedthrough Weeks 52 and 100.

There was significant improvement in DLQI scores in the ustekinumab groups as compared with placebo atweek 24, which was maintained through weeks 52 and 100. In PsA Study 2 there was a significant improvementin Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores in the ustekinumab groupswhen compared with placebo at week 24. The proportion of patients achieving a clinically significantimprovement in fatigue (4 points in FACIT-F) was also significantly greater in the ustekinumab groups comparedwith placebo. Improvements in FACIT scores were maintained through week 52.

The European Medicines Agency has deferred the obligation to submit the results of studies with ustekinumab inone or more subsets of the paediatric population with juvenile idiopathic arthritis (see section 4.2 for informationon paediatric use).

Ustekinumab has been shown to improve signs and symptoms, and health-related quality of life in paediatricpatients 6 years and older with plaque psoriasis.

Adolescent patients (12-17 years)

The efficacy of ustekinumab was studied in 110 paediatric patients aged 12 to 17 years with moderate to severeplaque psoriasis in a multicentre, phase 3, randomised, double-blind, placebo-controlled study (CADMUS).

Patients were randomised to receive either placebo (n =37), or the recommended dose of ustekinumab (seesection 4.2; n = 36) or half of the recommended dose of ustekinumab (n = 37) by subcutaneous injection at

Weeks 0 and 4 followed by every 12 week (q12w) dosing. At week 12, placebo-treated patients crossed over toreceive ustekinumab.

Patients with PASI ≥ 12, PGA ≥ 3 and BSA involvement of at least 10%, who were candidates for systemictherapy or phototherapy, were eligible for the study. Approximately 60% of the patients had prior exposure toconventional systemic therapy or phototherapy. Approximately11% of the patients had prior exposure to biologics.

The primary endpoint was the proportion of patients who achieved a PGA score of cleared (0) or minimal (1) atweek 12. Secondary endpoints included PASI 75, PASI 90, change from baseline in Children’s Dermatology

Life Quality Index (CDLQI), change from baseline in the total scale score of PedsQL (Paediatric Quality of Life

Inventory) at week 12. At week 12, subjects treated with ustekinumab showed significantly greater improvementin their psoriasis and health-related quality of life compared with placebo (Table 6).

All patients were followed for efficacy for up to 52 weeks following first administration of study agent. Theproportion of patients with a PGA score of cleared (0) or minimal (1) and the proportion achieving PASI 75showed separation between the ustekinumab treated group and placebo at the first post-baseline visit at week 4,reaching a maximum by week 12. Improvements in PGA, PASI, CDLQI and PedsQL were maintained throughweek 52 (Table 6).

Table 6: Summary of primary and secondary endpoints at week 12 and week 52

Paediatric psoriasis study (CADMUS) (Age 12-17)

Week 12 Week 52

Recommended dose Recommended dose

Placeboof Ustekinumab of Ustekinumab

N (%) N (%) N (%)

Patients randomised 37 36 35

PGA

PGA of cleared (0) or minimal2 (5.4%) a 20 (57.1%)(1) 25 (69.4%)

PGA of Cleared (0) 1 (2.7%) 17 (47.2%)a 13 (37.1%)

PASI

PASI 75 responders 4 (10.8%) 29 (80.6%)a 28 (80.0%)

PASI 90 responders 2 (5.4%) 22 (61.1%)a 23 (65.7%)

PASI 100 responders 1 (2.7%) 14 (38.9%)a 13 (37.1%)

CDLQI

CDLQI of 0 or 1b 6 (16.2%) 18 (50.0%)c 20 (57.1%)

PedsQL

Change from baseline Mean3.35 (10.04)d 8.03 (10.44)e 7.26 (10.92)(SD)a p < 0.001b CDLQI: The CDLQI is a dermatology instrument to assess the effect of a skin problem on thehealth-related quality of life in the paediatric population. CDLQI of 0 or 1 indicates no effect onchild’s quality of life.c p = 0.002d PedsQL: The PedsQL Total Scale Score is a general health-related quality of life measure developedfor use in children and adolescent populations. For the placebo group at week 12, N = 36e p = 0.028

During the placebo-controlled period through week 12, the efficacy of both the recommended and half of therecommended dose groups were generally comparable at the primary endpoint (69.4% and 67.6% respectively)although there was evidence of a dose response for higher level efficacy criteria (e.g. PGA of cleared (0), PASI90). Beyond week 12, efficacy was generally higher and better sustained in the recommended dose groupcompared with half of the recommended dosage group in which a modest loss of efficacy was more frequentlyobserved toward the end of each 12 week dosing interval. The safety profiles of the recommended dose and halfof the recommended dose were comparable.

Children (6-11 years)

The efficacy of ustekinumab was studied in 44 paediatric patients aged 6 to 11 years with moderate to severeplaque psoriasis in an open label, single-arm, multicentre, phase 3, study (CADMUS Jr.).

Patients were treated with the recommended dose of ustekinumab (see section 4.2; n = 44) by subcutaneousinjection at weeks 0 and 4 followed by every 12 week (q12w) dosing.

Patients with PASI ≥ 12, PGA ≥ 3 and BSA involvement of at least 10%, who were candidates for systemictherapy or phototherapy, were eligible for the study. Approximately 43% of the patients had prior exposure toconventional systemic therapy or phototherapy. Approximately 5% of the patients had prior exposure tobiologics.

The primary endpoint was the proportion of patients who achieved a PGA score of cleared (0) or minimal (1) atweek 12. Secondary endpoints included PASI 75, PASI 90, and change from baseline in Children’s Dermatology

Life Quality Index (CDLQI) at week 12. At week 12, subjects treated with ustekinumab showed clinicallymeaningful improvements in their psoriasis and health-related quality of life (Table 7).

All patients were followed for efficacy for up to 52 weeks following first administration of study agent. Theproportion of patients with a PGA score of cleared (0) or minimal (1) at week 12 was 77.3%. Efficacy (definedas PGA 0 or 1) was observed as early as the first post-baseline visit at week 4 and the proportion of subjects whoachieved a PGA score of 0 or 1 increased through week 16 and then remained relatively stable through week 52.

Improvements in PGA, PASI, and CDLQI were maintained through week 52 (Table 7).

Table 7: Summary of primary and secondary endpoints at week 12 and week 52

Paediatric psoriasis study (CADMUS Jr.) (Age 6-11)

Week 12 Week 52

Recommended dose of Recommended dose of

Ustekinumab Ustekinumab

N (%) N (%)

Patients enrolled 44 41

PGA

PGA of cleared (0) or minimal34 (77.3%) 31 (75.6%)(1)

PGA of cleared (0) 17 (38.6%) 23 (56.1%)

PASI

PASI 75 responders 37 (84.1%) 36 (87.8%)

PASI 90 responders 28 (63.6%) 29 (70.7%)

PASI 100 responders 15 (34.1%) 22 (53.7%)

CDLQIa

Patients with a CDLQI > 1 at baseline(N=39) (N=36)

CDLQI of 0 or 1 24 (61.5%) 21 (58.3%)a CDLQI: The CDLQI is a dermatology instrument to assess the effect of a skin problem on the health-related quality of life in the paediatric population. CDLQI of 0 or 1 indicates no effect on child’s qualityof life.

Crohn’s Disease

The safety and efficacy of ustekinumab was assessed in three randomized, double-blind, placebo- controlled,multicentre studies in adult patients with moderately to severely active Crohn’s disease (Crohn’s Disease

Activity Index [CDAI] score of ≥ 220 and ≤ 450). The clinical development program consisted of two 8-weekintravenous induction studies (UNITI-1 and UNITI-2) followed by a 44-week subcutaneous randomizedwithdrawal maintenance study (IM- UNITI) representing 52 weeks of therapy.

The induction studies included 1409 (UNITI-1, n = 769; UNITI-2 n = 640) patients. The primary endpoint forboth induction studies was the proportion of subjects in clinical response (defined as a reduction in CDAI scoreof ≥ 100 points) at week 6. Efficacy data were collected and analyzed through week 8 for both studies.

Concomitant doses of oral corticosteroids, immunomodulators, aminosalicylates and antibiotics were permittedand 75% of patients continued to receive at least one of these medications. In both studies, patients wererandomised to receive a single intravenous administration of either the recommended tiered dose ofapproximately 6 mg/kg (see section 4.2 of the IMULDOSA 130 mg Concentrate for solution for infusion SmPC),a fixed dose of 130 mg ustekinumab, or placebo at week 0.

Patients in UNITI-1 had failed or were intolerant to prior anti-TNFα therapy. Approximately48% of the patients had failed 1 prior anti-TNFα therapy and 52% had failed 2 or 3 prior anti- TNFα therapies.

In this study, 29.1% of the patients had an inadequate initial response (primary non-responders), 69.4%responded but lost response (secondary non-responders), and 36.4% were intolerant to anti- TNFα therapies.

Patients in UNITI-2 had failed at least one conventional therapy, including corticosteroids or immunomodulators,and were either anti-TNF-α naïve (68.6%) or had previously received but not failed anti-TNFα therapy (31.4%).

In both UNITI-1 and UNITI-2, a significantly greater proportion of patients were in clinical response andremission in the ustekinumab treated group compared to placebo (Table 8). Clinical response and remission weresignificant as early as week 3 in ustekinumab treated patients and continued to improve through week 8. In theseinduction studies, efficacy was higher and better sustained in the tiered dose group compared to the 130 mg dosegroup, and tiered dosing is therefore the recommended intravenous induction dose.

Table 8: Induction of Clinical Response and Remission in UNITI-1 and UNITI 2

UNITI-1* UNITI-2**

Placebo Recommended Placebo Recommended

N = 247 dose of N = 209 dose ofustekinumab N ustekinumab N= 249 = 209

Clinical Remission, week 8 18 (7.3%) 52 (20.9%)a 41 (19.6%) 84 (40.2%)a

Clinical Response (100 point), week 6 53 (21.5%) 84 (33.7%)b 60 (28.7%) 116 (55.5%)a

Clinical Response (100 point), week 8 50 (20.2%) 94 (37.8%)a 67 (32.1%) 121 (57.9%)a70 Point Response, week 3 67 (27.1%) 101 (40.6%)b 66 (31.6%) 106 (50.7%)a70 Point Response, week 6 75 (30.4%) 109 (43.8%)b 81 (38.8%) 135 (64.6%)a

Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI score by atleast 100 points or being in clinical remission70 point response is defined as reduction in CDAI score by at least 70 points

* Anti-TNFα failures

** Conventional therapy failuresa p < 0.001b p < 0.01

The maintenance study (IM-UNITI), evaluated 388 patients who achieved 100 point clinical response at week 8of induction with ustekinumab in studies UNITI-1 and UNITI-2. Patients were randomized to receive asubcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, 90 mg ustekinumab every 12weeks or placebo for 44 weeks (for recommended maintenance posology, see section 4.2).

Significantly higher proportions of patients maintained clinical remission and response in the ustekinumab treatedgroups compared to the placebo group at week 44 (see Table 9).

Table 9: Maintenance of Clinical Response and Remission in IM-UNITI (week 44; 52 weeks from initiation of theinduction dose)

Placebo* 90 mg 90 mgustekinumab ustekinumabevery 8 weeks every 12 weeks

N = 131†

N = 128† N = 129†

Clinical Remission 36% 53%a 49%b

Clinical Response 44% 59%b 58%b

Corticosteroid-Free Clinical Remission 30% 47%a 43%c

Clinical Remission in patients:

in remission at the start of maintenance 46% (36/79) 67% (52/78)a 56% (44/78)therapywho entered from study CRD3002‡ 44% (31/70) 63% (45/72)c 57% (41/72)who are Anti-TNFα naïve 49% (25/51) 65% (34/52)c 57% (30/53)who entered from study CRD3001§ 26% (16/61) 41% (23/56) 39% (22/57)

Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI of at least100 points or being in clinical remission

* The placebo group consisted of patients who were in response to ustekinumab and were randomized toreceive placebo at the start of maintenance therapy.† Patients who were in 100 point clinical response to ustekinumab at start of maintenance therapy‡ Patients who failed conventional therapy but not anti-TNFα therapy§ Patients who are anti-TNFα refractory/intoleranta p < 0.01b p < 0.05c nominally significant (p < 0.05)

In IM-UNITI, 29 of 129 patients did not maintain response to ustekinumab when treated every 12 weeks and wereallowed to dose adjust to receive ustekinumab every 8 weeks. Loss of response was defined as a CDAI score ≥220 points and a ≥ 100 point increase from the CDAI score at baseline. In these patients, clinical remission wasachieved in 41.4% of patients 16 weeks after dose adjustment.

Patients who were not in clinical response to ustekinumab induction at week 8 of the UNITI-1 and UNITI-2induction studies (476 patients) entered into the non-randomized portion of the maintenance study (IM-UNITI)and received a 90 mg subcutaneous injection of ustekinumab at that time. Eight weeks later, 50.5% of thepatients achieved clinical response and continued to receive maintenance dosing every 8 weeks; among thesepatients with continued maintenance dosing, a majority maintained response (68.1%) and achieved remission(50.2%) at week 44, at proportions that were similar to the patients who initially responded to ustekinumabinduction.

Of 131 patients who responded to ustekinumab induction, and were randomized to the placebo group at the startof the maintenance study, 51 subsequently lost response and received 90 mg ustekinumab subcutaneously every8 weeks. The majority of patients who lost response and resumed ustekinumab did so within 24 weeks of theinduction infusion. Of these 51 patients,70.6% achieved clinical response and 39.2% percent achieved clinical remission 16 weeks after receiving thefirst subcutaneous dose of ustekinumab.

In IM-UNITI, patients who completed the study through week 44 were eligible to continue treatment in a studyextension. Among the 567 patients who entered on and were treated with ustekinumab in the study extension,clinical remission and response were generally maintained through week 252 for both patients who failed TNF-therapies and those who failed conventional therapies.

No new safety concerns were identified in this study extension with up to 5 years of treatment in patients with

Crohn’s Disease.

Endoscopy

Endoscopic appearance of the mucosa was evaluated in 252 patients with eligible baseline endoscopic diseaseactivity in a substudy. The primary endpoint was change from baseline in Simplified Endoscopic Disease

Severity Score for Crohn’s Disease (SES-CD), a composite score across 5 ileo- colonic segments ofpresence/size of ulcers, proportion of mucosal surface covered by ulcers, proportion of mucosal surface affectedby any other lesions and presence/type of narrowing/strictures. At week 8, after a single intravenous inductiondose, the change in SES-CD score was greater in the ustekinumab group (n = 155, mean change = -2.8) than inthe placebo group (n = 97, mean change = -0.7, p = 0.012).

Fistula Response

In a subgroup of patients with draining fistulas at baseline (8.8%; n = 26), 12/15 (80%) of ustekinumab-treatedpatients achieved a fistula response over 44 weeks (defined as ≥ 50% reduction from baseline of the inductionstudy in the number of draining fistulas) compared to5/11 (45.5%) exposed to placebo.

Health-related quality of life was assessed by Inflammatory Bowel Disease Questionnaire (IBDQ) and SF-36questionnaires. At week 8, patients receiving ustekinumab showed statistically significantly greater andclinically meaningful improvements on IBDQ total score and SF-36 Mental Component Summary Score in both

UNITI-1 and UNITI-2, and SF-36 Physical Component Summary Score in UNITI-2, when compared to placebo.

These improvements were generally better maintained in ustekinumab-treated patients in the IM-UNITI studythrough week 44 when compared to placebo. Improvement in health-related quality of life was generallymaintained during the extension through week 252.

Antibodies to ustekinumab may develop during ustekinumab treatment and most are neutralising. The formationof anti-ustekinumab antibodies is associated with both increased clearance and reduced efficacy of ustekinumab,except in patients with Crohn’s disease where no reduced efficacy was observed. There is no apparentcorrelation between the presence of anti-ustekinumab antibodies and the occurrence of injection site reactions.

The European Medicines Agency has deferred the obligation to submit the results of studies with ustekinumab inone or more subsets of the paediatric population in Crohn’s Disease (see section 4.2 for information on paediatricuse).

The median time to reach the maximum serum concentration (tmax) was 8.5 days after a single 90 mgsubcutaneous administration in healthy subjects. The median tmax values of ustekinumab following a singlesubcutaneous administration of either 45 mg or 90 mg in patients with psoriasis were comparable to thoseobserved in healthy subjects.

The absolute bioavailability of ustekinumab following a single subcutaneous administration was estimated to be57.2% in patients with psoriasis.

Median volume of distribution during the terminal phase (Vz) following a single intravenous administration topatients with psoriasis ranged from 57 to 83 mL/kg.

The exact metabolic pathway for ustekinumab is unknown.

Median systemic clearance (CL) following a single intravenous administration to patients with psoriasis rangedfrom 1.99 to 2.34 mL/day/kg. Median half-life (t1/2) of ustekinumab was approximately 3 weeks in patients withpsoriasis, psoriatic arthritis, Crohn’s disease, ranging from 15 to 32 days across all psoriasis and psoriatic arthritisstudies. In a population pharmacokinetic analysis, the apparent clearance (CL/F) and apparent volume ofdistribution (V/F) were 0.465 l/day and 15.7 l, respectively, in patients with psoriasis. The CL/F of ustekinumabwas not impacted by gender. Population pharmacokinetic analysis showed that there was a trend towards a higherclearance of ustekinumab in patients who tested positive for antibodies to ustekinumab.

Dose linearity

The systemic exposure of ustekinumab (Cmax and AUC) increased in an approximately dose- proportionalmanner after a single intravenous administration at doses ranging from 0.09 mg/kg to4.5 mg/kg or following a single subcutaneous administration at doses ranging from approximately24 mg to 240 mg in patients with psoriasis.

Single dose versus multiple doses

Serum concentration-time profiles of ustekinumab were generally predictable after single or multiplesubcutaneous dose administrations. In patients with psoriasis, steady-state serum concentrations of ustekinumabwere achieved by week 28 after initial subcutaneous doses at Weeks 0 and 4 followed by doses every 12 weeks.

The median steady-state trough concentration ranged from 0.21 μg/mL to 0.26 μg/mL (45 mg) and from 0.47μg/mL to 0.49 μg/mL (90 mg). There was no apparent accumulation in serum ustekinumab concentration overtime when given subcutaneously every 12 weeks.

In patients with Crohn’s disease, following an intravenous dose of ~6 mg/kg, starting at week 8, subcutaneousmaintenance dosing of 90 mg ustekinumab was administered every 8 or 12 weeks. Steady state ustekinumabconcentration was achieved by the start of the second maintenance dose. In patients with Crohn’s disease, mediansteady-state trough concentrations ranged from 1.97 μg/mL to 2.24 μg/mL and from 0.61 μg/mL to 0.76 μg/mLfor 90 mg ustekinumab every 8 weeks or every 12 weeks respectively.

Impact of weight on pharmacokinetics

In a population pharmacokinetic analysis using data from patients with psoriasis, body weight was found to bethe most significant covariate affecting the clearance of ustekinumab. The median CL/F inpatients with weight >100 kg was approximately 55% higher compared to patients with weight ≤ 100 kg. The median V/F in patientswith weight > 100 kg was approximately 37% higher as compared to patients with weight ≤ 100 kg. The mediantrough serum concentrations of ustekinumab in patients with higher weight (> 100 kg) in the 90 mg group werecomparable to those in patients with lower weight (≤ 100 kg) in the 45 mg group. Similar results were obtainedfrom a confirmatory population pharmacokinetic analysis using data from patients with psoriatic arthritis.

Dosing frequency adjustment

In patients with Crohn’s disease, based on observed data and population PK analyses, randomized subjects wholost response to treatment had lower serum ustekinumab concentrations over time compared with subjects whodid not lose response. In Crohn’s disease, dose adjustment from 90 mg every 12 weeks to 90 mg every 8 weekswas associated with an increase in trough serum ustekinumab concentrations and an accompanying increase inefficacy.

No pharmacokinetic data are available in patients with impaired renal or hepatic function. No specific studieshave been conducted in elderly patients.

The pharmacokinetics of ustekinumab were generally comparable between Asian and non-Asian patients withpsoriasis.

In patients with Crohn’s disease, variability in ustekinumab clearance was affected by body weight, serumalbumin level, sex, and antibody to ustekinumab status while body weight was the main covariate affecting thevolume of distribution. Additionally in Crohn’s disease, clearance was affected by C-reactive protein, TNFantagonist failure status and race (Asian versus non-Asian). The impact of these covariates was within ± 20% ofthe typical or reference value of the respective PK parameter, thus dose adjustment is not warranted for thesecovariates. Concomitant use of immunomodulators did not have a significant impact on ustekinumabdisposition.

In the population pharmacokinetic analysis, there were no indications of an effect of tobacco or alcohol on thepharmacokinetics of ustekinumab.

Serum ustekinumab concentrations in paediatric psoriasis patients 6 to 17 years of age, treated with therecommended weight-based dose were generally comparable to those in the adult psoriasis population treatedwith the adult dose. Serum ustekinumab concentrations in paediatric psoriasis patients12-17 years of age(CADMUS) treated with half of the recommended weight- based dose were generally lower than those in adults.

Regulation of CYP450 enzymes

The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro study usinghuman hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did not alter human CYP450enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4; see section 4.5). A phase 1, open-label, druginteraction study, Study CNTO1275CRD1003, was conducted to evaluate the effect of ustekinumab oncytochrome P450 enzyme activities following induction and maintenance dosing in patients withactive Crohn’s disease (n=18). No clinically significant changes in exposure of caffeine (CYP1A2substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), dextromethorphan(CYP2D6 substrate), or midazolam (CYP3A substrate) were observed when used concomitantly withustekinumab at the approved recommended dosing in patients with Crohn’s disease (see section 4.5).

Non-clinical data reveal no special hazard (e.g. organ toxicity) for humans based on studies of repeated-dosetoxicity and developmental and reproductive toxicity, including safety pharmacology evaluations. Indevelopmental and reproductive toxicity studies in cynomolgus monkeys, neither adverse effects on malefertility indices nor birth defects or developmental toxicity were observed. No adverse effects on female fertilityindices were observed using an analogous antibody to IL-12/23 in mice.

Dose levels in animal studies were up to approximately 45-fold higher than the highest equivalent dose intendedto be administered to psoriasis patients and resulted in peak serum concentrations in monkeys that were morethan 100-fold higher than observed in humans.

Carcinogenicity studies were not performed with ustekinumab due to the lack of appropriate models for anantibody with no cross-reactivity to rodent IL-12/23 p40.

L-histidine

L-histidine hydrochloride monohydrate

Polysorbate 80 (E433)

Sucrose

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

IMULDOSA 45 mg solution for injection in pre-filled syringe 2 years.

IMULDOSA 90 mg solution for injection in pre-filled syringe 2 years.

Individual pre-filled syringes may be stored at room temperature up to 30°C for a maximum single period of upto 30 days in the original carton in order to protect from light. Record the date when the pre-filled syringe is firstremoved from the refrigerator and the discard date in the spaces provided on the outer carton. The discard datemust not exceed the original expiry date printed on the carton. Once a syringe has been stored at roomtemperature (up to 30°C), it should not be returned to the refrigerator. Discard the syringe if not used within 30days at room temperature storage or by the original expiry date, whichever is earlier.

Store in a refrigerator (2°C - 8°C). Do not freeze.

Keep the pre-filled syringe in the outer carton in order to protect from light.

If needed, individual pre-filled syringes may be stored at room temperature up to 30°C (see section 6.3).

IMULDOSA 45 mg solution for injection in pre-filled syringe0.5 mL solution in a type I glass 1 mL syringe with a fixed stainless-steel 29-gauge needle, extended fingerflanges and a needle cover with an elastomeric needle shield and a plastic rigid needle shield. The syringe is fittedwith automatic needle guard.

IMULDOSA 90 mg solution for injection in pre-filled syringe1 mL solution in a type I glass 1 mL syringe with a fixed stainless-steel 29-gauge needle, extendedfinger flanges and a needle cover with an elastomeric needle shield and a plastic rigid needle shield.

The syringe is fitted with automatic needle guard.

IMULDOSA is available in a pack of 1 pre-filled syringe.

The solution in the IMULDOSA pre-filled syringe should not be shaken. The solution should be visuallyinspected for particulate matter or discolouration prior to subcutaneous administration. The solution iscolourless to slightly yellow and clear to slightly opalescent. This appearance is not unusual for proteinaceoussolutions. The medicinal product should not be used if the solution is discoloured or cloudy, or if foreignparticulate matter is present. Before administration, IMULDOSA should be allowed to reach room temperature(approximately half an hour). Detailed instructions for use are provided in the package leaflet.

IMULDOSA does not contain preservatives; therefore any unused medicinal product remaining in the syringeshould not be used. IMULDOSA is supplied as a sterile, single- use pre-filled syringe. The syringe and needlemust never be re-used. Any unused medicinal product or waste material should be disposed of in accordancewith local requirements.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n

Edifici Est, 6a Planta08039 Barcelona

Spain

EU/1/24/1872/001

EU/1/24/1872/002

Date of first authorization: 12 December 2024

Detailed information on this medicinal product is available on the website of the European

Medicines Agency http://www.ema.europa.eu/